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    Clinical Trial Results:
    COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI trial

    Summary
    EudraCT number
    		 2015-001000-58
    Trial protocol
    		 ES  
    Global end of trial date
    29 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2021
    First version publication date
    20 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COMBAT-MI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02404376
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HOSPITAL UNIVERSITARI VALL D`HEBRON
    Sponsor organisation address
    PASSEIG VALL D`HEBRON 119-129, BARCELONA, Spain, 08035
    Public contact
    Ignacio Ferreira González, Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR), +34 9327461346134, nachoferreira@secardiologia.es
    Scientific contact
    Ignacio Ferreira González, Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR), +34 9327461346134, nachoferreira@secardiologia.es
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effectiveness of combination therapy with RIC and exenatide to limit MI size in patients with STEMI receiving pPCI.
    Protection of trial subjects
    measures to minimise pain
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 378
    Worldwide total number of subjects
    378
    EEA total number of subjects
    378
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    219
    From 65 to 84 years
    150
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients eligible were enrolled in the catheterization laboratory and were randomly assigned to one of four groups.

    Pre-assignment
    Screening details
    		 Patients may be considered elegible by Haemodinamics after verification of eligible criteria and exclusion criteria (screening).

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PLACEBO+RIC
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    All patients will receive saline, 180mL was intravenously administered, prior to the PPCI, at a flow rate of 72mL/h. After 15 min, the flow rate was reduced to 26mL/h and maintained for additional 6 hours.

    Arm title
    		 PLACEBO+ SHAM-RIC
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients receive saline , 180mL was intravenously administered, prior to the PPCI, at a flow rate of 72mL/h. After 15 min, the flow rate was reduced to 26mL/h and maintained for additional 6 hours.

    Arm title
    		 EXENATIDE+RIC
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EXENATIDE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients will receive intravenous infusion of exenatide (18μg) diluted in saline (vehicle, 180mL) was intravenously administered, prior to the PPCI, at a flow rate of 72mL/h (0.12μg/min). After 15 min, the flow rate was reduced to 26mL/h (0.043μg/min) and maintained for additional 6 hours.

    Arm title
    		 EXENATIDE+SHAM RIC
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EXENATIDE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients will receive intravenous infusion of exenatide (18μg) diluted in saline (vehicle, 180mL) was intravenously administered, prior to the PPCI, at a flow rate of 72mL/h (0.12μg/min). After 15 min, the flow rate was reduced to 26mL/h (0.043μg/min) and maintained for additional 6 hours.

    Number of subjects in period 1
    		PLACEBO+RIC PLACEBO+ SHAM-RIC EXENATIDE+RIC EXENATIDE+SHAM RIC
    Started
    96
    93
    91
    98
    Completed
    54
    58
    48
    62
    Not completed
    42
    35
    43
    36
         Primary Outcome not performed
    1
    2
    1
    1
         CRM not performed
    2
    3
    7
    5
         Exclusion Criteria
    39
    30
    35
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PLACEBO+RIC
    Reporting group description
    		 -

    Reporting group title
    PLACEBO+ SHAM-RIC
    Reporting group description
    		 -

    Reporting group title
    EXENATIDE+RIC
    Reporting group description
    		 -

    Reporting group title
    EXENATIDE+SHAM RIC
    Reporting group description
    		 -

    Reporting group values
    		 PLACEBO+RIC PLACEBO+ SHAM-RIC EXENATIDE+RIC EXENATIDE+SHAM RIC Total
    Number of subjects
    		 96 93 91 98 378
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 52 60 47 52 211
        From 65-84 years
    		 43 32 40 43 158
        85 years and over
    		 1 1 4 3 9
    Gender categorical
    Units: Subjects
        Female
    		 15 10 15 39 79
        Male
    		 81 83 76 59 299
    Subject analysis sets

    Subject analysis set title
    Placebo+ RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo+ RIC

    Subject analysis set title
    Placebo+ Sham RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo+ Sham RIC

    Subject analysis set title
    EXENATIDE+ RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ENENATIDE+ RIC

    Subject analysis set title
    EXENATIDE+ Sham RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    EXENATIDE+ Sham RIC

    Subject analysis sets values
    		 Placebo+ RIC Placebo+ Sham RIC EXENATIDE+ RIC EXENATIDE+ Sham RIC
    Number of subjects
    54
    58
    48
    62
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    33
    40
    27
    36
        From 65-84 years
    21
    18
    19
    25
        85 years and over
    0
    0
    2
    1
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    6
    8
    8
    14
        Male
    48
    50
    40
    48

    End points

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    End points reporting groups
    Reporting group title
    PLACEBO+RIC
    Reporting group description
    		 -

    Reporting group title
    PLACEBO+ SHAM-RIC
    Reporting group description
    		 -

    Reporting group title
    EXENATIDE+RIC
    Reporting group description
    		 -

    Reporting group title
    EXENATIDE+SHAM RIC
    Reporting group description
    		 -

    Subject analysis set title
    Placebo+ RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo+ RIC

    Subject analysis set title
    Placebo+ Sham RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo+ Sham RIC

    Subject analysis set title
    EXENATIDE+ RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ENENATIDE+ RIC

    Subject analysis set title
    EXENATIDE+ Sham RIC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    EXENATIDE+ Sham RIC

    Primary: Myocardial Infarct Size measured by late gadolinium enhancement in CMRI 3-7 days after pPCI, and expressed as percent of left ventricular mass

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    End point title
    		 Myocardial Infarct Size measured by late gadolinium enhancement in CMRI 3-7 days after pPCI, and expressed as percent of left ventricular mass
    End point description
    End point type
    Primary
    End point timeframe
    3-7 days
    End point values
    		 PLACEBO+RIC PLACEBO+ SHAM-RIC EXENATIDE+RIC EXENATIDE+SHAM RIC
    Number of subjects analysed
    54
    58
    48
    62
    Units: percentage
    54
    58
    48
    62
    Statistical analysis title
    		 Factorial
    Comparison groups
    PLACEBO+RIC v PLACEBO+ SHAM-RIC v EXENATIDE+RIC v EXENATIDE+SHAM RIC
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 > 0.05 [2]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [1] - Two by two factorial analysis
    [2] - Negative clinical trial

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 year
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo+ RIC
    Reporting group description
    		 -

    Reporting group title
    Placebo+ RIC
    Reporting group description
    		 -

    Reporting group title
    EXENATIDE + RIC
    Reporting group description
    		 -

    Reporting group title
    EXENATIDE + Sham RIC
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo+ RIC Placebo+ RIC EXENATIDE + RIC EXENATIDE + Sham RIC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 54 (12.96%)
    15 / 58 (25.86%)
    13 / 48 (27.08%)
    7 / 62 (11.29%)
         number of deaths (all causes)
    1
    1
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Death
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
    0 / 48 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
    2 / 48 (4.17%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    4 / 54 (7.41%)
    8 / 58 (13.79%)
    8 / 48 (16.67%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Transient ischaemic attack
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
    0 / 48 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
    3 / 48 (6.25%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placebo+ RIC Placebo+ RIC EXENATIDE + RIC EXENATIDE + Sham RIC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 54 (12.96%)
    15 / 58 (25.86%)
    7 / 48 (14.58%)
    6 / 62 (9.68%)
    Cardiac disorders
    Percutaneous coronary intervention
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
    2 / 48 (4.17%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 54 (1.85%)
    6 / 58 (10.34%)
    2 / 48 (4.17%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    0
    0
    Arrhythmia supraventricular
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    5 / 54 (9.26%)
    4 / 58 (6.90%)
    3 / 48 (6.25%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2016
    Amendment nº1 Update of participating centers Number of patients is increased Modification of extension of time to perform the CMR
    07 Mar 2017
    Amendment nº2 Update of CMR machine Update of participating Investigators sites
    31 May 2017
    Amendment nº3 Update of participating investigator sites Revision of patient`s information letter
    08 Mar 2018
    Amendment nº4 Number of patients is increased
    19 Sep 2019
    Amendment nº5 Updated of participating investigator site

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial could not be finished according with the prespecified sample size because of recruitment problems. Final sample size included in the analyses underpowered.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33495853
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